Fluticasone propionate belongs to a class of androstane 17β-carbothioic esters which are well-known in the art as antiinflammatories. Because of the therapeutic usefulness of these compounds, there is sustained interest in improving the synthesis of androstane 17β-carbothioic esters in general, and fluticasone propionate in particular.
Prior art such as U.S. Pat. Nos. 4,188,385, 4,198,403, 4,335,121, and 4,578,221; British patents 2,088,877 and 2,137,206; and published Israeli patent application IL 109,656-A1 teach the synthesis of fluticasone propionate from commercial grade flumethasone. These syntheses involve complicating factors such as chromatography of intermediates, low-yielding steps, and high pressure addition of chlorofluoromethane.
Commercial grade flumethasone ((6α, 11β, 16α)-6,9-difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione) typically contains from about 0.5% to 2% of (6α,11β,16α)-6-chloro-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione as an impurity (hereinafter referred to as the Cl impurity), the removal of which is achieved by column chromatography, a method not amenable to large scale manufacture.
Conversion of the 17β-carboxylic acid of 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylic acid to a carbothioic acid is also problematic. General methods for the conversion of carboxylic acids to carbothioic acids include reaction of activated carboxylic acids and a sulfide source (Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, New York, 1992; and U.S. Pat. No. 4,578,221) and application of thiocarbamate hydrolysis chemistry to thiocarbamylanhydrides (Bull. Chem. Soc. Jpn., 1977, 50(11), 3071; J. Ind. Chem. Soc., 1977, 52, 150; J. Org. Chem., 1966, 31, 3980; Org. Syn., 1988, Collective Volume VI, 824; J. Am. Chem. Soc. 1947, 69, 2682; and Synlett., 1996, 11, 1054). Use of these methods in the synthesis of fluticasone propionate, however, provide only modest yields due to incompatibility of the reaction conditions with other groups on the molecule (J. Med. Chem., 1984, 37(22) 3171 and J. Org. Chem. 1986, 51(12) 2315).
Direct conversion of the carbothioic acid group of androstane 17β-carbothioic acids to a carbothiolate esters is achieved by reaction of the carbothioic acids, chlorofluoromethane, and base at high pressures, another method which is not amenable to large scale manufacture.
Thus, there is a continuing need in the pharmaceutical manufacturing industry for an efficient method for the conversion of carboxylic acids to carbothioic acid esters which is applicable to the large scale conversion of androstane 17β-carboxylic acids to androstane 17β-carbothioic esters in general and fluticasone propionate, in particular.